Neonatal-onset carbamoyl phosphate synthetase I deficiency

Abstract

Rationale:The carbamoyl phosphate synthetase I deficiency (CPS1D) was rare and hard to diagnose due to its atypical symptoms. Brain magnetic resonance imaging (MRI) was typically unavailable in other reports because most patients died before diagnosis was confirmed. Furthermore, it was found a new mutation that had not been described previously.Patient concerns:This is a case of neonatal-onset CPS1D with nonspecific clinical manifestations and deteriorating rapidly. Poor feeding, low activity, and tachypnoea were observed, with rapid progression on day 2 after birth. Severe systematic infection was considered first. However, blood culture and cerebrospinal fluid examination were negative. Symptoms were relief temporarily. Then seizure and tachypnoea reappeared as intravenous amino acids were provided. Further examination indicated severe hyperammonemia (serum ammonia level >500mmol/L). Brain MRI showed diffused white matter lesions.Diagnoses:Genetic analysis revealed 2 heterozygous mutations in the CPS1 gene: c.2407C>G (p.803, R>G) in exon 20 and C.323G>A (p.108, G>E) in exon 4. The diagnosis of CSP1D was confirmed.Interventions:Fasting, the withdrawal of amino acids and plans to treat hyperammonemia were immediately implemented.Outcomes:The parents decided to discontinue medical care.Lessons:Many CPS1D patients died before the diagnoses are confirmed due to its sudden onset, rapid deterioration, atypical symptoms, and low morbidity. Once hyperammonemia is confirmed, blood and urea amino acid analysis in combination with genetic examinations should be performed as early as possible, this approach would help establish diagnoses at an early stage and thus contribute to reducing mortality and improving prognosis.

Two novel CPS1 mutations in a case of carbamoyl phosphate synthetase 1 deficiency causing hyperammonemia and leukodystrophy

“…Mutations in the large‐subunit‐like moiety involving the two phosphorylation domains and the NAG binding domain are highly important to the activation of the enzyme and more likely to be pathogenic. CPS1 defects located in the NAG binding domain (c.4088_4099del), bicarbonate phosphorylation domain (c.1799G>A), carbamate phosphorylation domain (c.3443T>A), ISD subdomain (c.323G>A), and even the function unknown domain (c.2537C>T, c.2407C>G) have already been reported in the Chinese CPS1D cohorts . The two novel mutations in this study, c.173G>T (p.G58V) and c.796G>A (p.G266R), are, respectively, fall into the ISD and GSD subdomains in the 40‐kDa small‐subunit‐like domain of CPS1, which has been proved to lost its role in binding and hydrolyzing glutamine in human body .…”

“…Carbamoyl phosphate synthetase 1 deficiency (CPS1D; MIM237300) is an autosomal recessive genetic disorder, characterized by devastating metabolic disease dominated by severe hyperammonemia, and some patients also suffer from brain white matter changes . The time of onset presents as either in neonates or in a more insidious late‐onset.…”

“…The morbidity of CPS1D is estimated 1:50 000‐1:300 000 in worldwide, of which 1:800 000 in Japan and 1:50 000‐1:100 000 in European population . To our knowledge, the frequency of CPS1D has not been observed in Chinese cohorts and only three Chinese patients with CPS1D were reported …”

“…CPS1 maps on chromosome 2q35 and comprises 38 exons that span more than 120 kb region, which encodes 1500 amino acids . More than 240 changes distributed along the whole CPS1 sequence, including missense, nonsense, deletion or insertion, and other types of mutations resulting in enzyme destruction, have been confirmed in unrelated individuals with CPS1D in the world population, while only 6 mutations were reported in Chinese patients …”

“…is an autosomal recessive genetic disorder, characterized by devastating metabolic disease dominated by severe hyperammonemia, and some patients also suffer from brain white matter changes. 1,2 The time of onset presents as either in neonates or in a more insidious late-onset. The morbidity of CPS1D is estimated 1:50 000-1:300 000 in worldwide, of which 1:800 000 in Japan and 1:50 000-1:100 000 in European population.…”